Obesity is a public health crisis in the U.S. by virtue of its causal role in and/or association with a variety of diseases including: type 2 diabetes, metabolic syndrome, heart disease, and cancer. Obesity is caused by a defect in energy balance, where calorie intake from food chronically exceeds expenditure. White adipose tissue is highly adapted to store the excess food energy in the form of triglycerides (fat). Mammals are also equipped with brown adipose which dissipates chemical energy to produce heat. Many studies document the ability of brown fat to counteract obesity and diabetes by raising whole body energy expenditure. We recently identified PRDM16 as a transcriptional regulator selectively expressed in brown versus white fat. Strikingly, PRDM16 is able to induce a near complete program of brown fat differentiation when expressed in white fat progenitors. Defining the molecular pathways that specifically regulate brown adipose development through PRDM16 could thus provide realistic therapeutic targets to reduce obesity. In this proposal, we explore the in vivo physiological role of PRDM16 in development and obesity;and investigate the mechanistic basis for its function in brown fat determination. Specifically, in aim 1, a genetic and a cell therapy approach is used to test whether PRDM16 expression in white fat can protect against obesity. In aim 2, biochemical studies are employed to elucidate how PRDM16 drives the program of brown fat differentiation via its interaction with PPAR transcription factors. Finally, aim 3 is to determine the physiological role of PRDM16 in development and metabolism by studying PRDM16-deficient mice. PUBLIC HEALTH RELEVANCE: The prevalence of obesity and its role in promoting many diseases make it the number one public health issue in the U.S. Raising energy expenditure by increasing the formation or function of brown fat is a viable approach to reduce obesity. In this study, we directly test whether PRDM16 can be used to counteract obesity and hope that this will provide the scientific basis for finding pharmacological agents that increase PRDM16 function. In addition, we investigate the mechanistic basis for PRDM16 action in stimulating brown fat development, which is likely to reveal additional therapeutic targets for fighting obesity.